SELECTIVE NEURONAL LOSS AND ITS SEQUELAE--A MODEL

Project: Research project

Description

Nerve cell degeneration and loss are pivotal events in most hereditary
diseases of the central nervous system. Among these diseases are the
heredo-degenerative ataxias, Parkinson's disease, and Alzheimer's
disease. in the heredo-degenerative ataxias, the degeneration of Purkinje
cells (PC), which are essential for normal motor functions, leads to
incoordination. In Parkinson's disease, degeneration of midbrain
dopamine (DA) neurons, that participate in a variety of motor functions
and mental processes, leads to tremor, rigidity, bradykinesia and deficit
of posture. Neuronal loss triggers a cascade of transsynaptic changes,
whose mechanisms are poorly understood. Understanding the mechanisms of
such degeneration is best achieved by studying a given neuronal
population prior to or early in the degenerative process. An analysis of
the cascade of transsynaptic changes can be best achieved in natural
models of degenerative diseases in which nerve cell loss and the
transneuronal sequelae occur in a well known and predictable time
sequence. In the Purkinje cell degeneration (pcd) and weaver (wv) mutant
mice, loss of PC and of midbrain (DA) neurons, respectively, are among
the major phenotypic events and they occur in a fixed time frame. A long
term goal of this project is to investigate the mechanisms leading to
cell loss at the cellular and molecular level and to attempt to
understand the primary defect. We will construct cDNA libraries from
cerebella of pcd mutants at the onset of Purkinje cell degeneration and
we will isolate clones that are differentially expressed. These cDNAs
will be evaluated by sequencing and their cell of origin determined by in
situ hybridization. We will begin molecular/biochemical characterization
of the pcd-induced neurodegenerative cascade by following the expression
of these clones, PC markers and cytoskeletal markers during the disease
and we will attempt to clone the pcd cDNA. For the wv mutant, studies
will be carried out in order to determine the effect of DA losses on the
GABAergic striatal interneurons and efferents and on the striato-pallidal
enkephalin and the striato-nigral dynorphin systems. In addition, we
will determine the significance of the increased content of serotonin in
the striatum of the wv mutant. Since the trophic interactions between DA
neurons and their target cells in the establishment and maintenance of
the nigrostriatal DA projection are not understood, we will utilize the
three-dimensional reaggregate tissue culture system to investigate
whether the loss of DA neurons observed in the wv mutant is due to a
defect in the DA neurons themselves, or in their target cells. Embryonic
brain cells from wv and normal (non-weaver) mice will be cocultured to
test whether target cells from normal mice can promote the survival of
the wv DA neuron. Conversely, target cells from wv mice will be assessed
for their ability to produce a loss of DA cells from normal mice. In
addition, we propose to use the wv mouse as a means of obtaining a
selected population of medial DA neurons, cells which project to limbic
and cortical areas and are relatively spared in wv mutants, for the
purposes of generating an immortalized DA cell line by somatic cell
hybridization. The availability of such a DA cell line will be an
important model for examining DA neuronal target recognition and
neurotoxicity.
StatusFinished
Effective start/end date12/1/796/30/02

Funding

  • National Institutes of Health: $487,262.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $212,437.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $50,000.00
  • National Institutes of Health: $456,636.00
  • National Institutes of Health: $577,019.00
  • National Institutes of Health

Fingerprint

Purkinje Cells
Neurons
Substantia Nigra
Dopaminergic Neurons
Central Nervous System
Nerve Degeneration
Neurologic Mutant Mice
Biological Phenomena
Tissue Transplantation
Cerebellum
Homozygote
Heterozygote
Epigenomics
Ataxia
Cholinergic Agents
Genes
Dopamine
Neurotransmitter Agents
Clone Cells
Electron Microscopy

Keywords

  • Medicine(all)
  • Neuroscience(all)